Clinical pharmacology of parenteral use of antiepileptic drugs.

Intravenous (i.v.) administration of antiepileptic drugs (AEDs) produces the most rapid onset of action, as it is delivered directly into the bloodstream and immediately produces maximal plasma concentration (C0 = Cmax). In addition to its therapeutic value, i.v. administration is essential in investigating the pharmacokinetics (PK) or clinical pharmacology of drugs, as it bypasses absorption and focuses on the disposition (distribution plus elimination) of drugs. Consequently due to its direct delivery of drugs to the blood, i.v. injection or infusion is the reference route for absolute bioavailability calculations. Other parenteral routes like intramuscular (im) or subcutaneous (sc) administration are examples of extravascular (ev) administration involving absorption processes and therefore, drug plasma profiles produced are similar to the one obtained following oral administration of conventional (immediate release) formulations. Most AEDs exhibit linear (concentration-independent) PK and therefore their major PK parameters: clearance (CL), apparent volume of distribution (V), and half-life (t1/2) are not affected by the route of administration or by the rate or extent of absorption (Bialer and Cloyd, 1995). Changes in route of administration or in the parenteral (ev) formulation only affect the extent and rate of absorption, whereas the disposition is an intrinsic property of the AED or the active entity. Similar to oral formulations, parenteral preparations intended for im or sc injections may be formulated to have a rapid or slow rate of absorption. The preferred parenteral preparations are aqueous solutions that generally distribute rapidly from the administration site. Hydroalcoholic, oily, or suspension vehicles may result in slow and sustained absorption, side effect of the nonaqueous solvents (e.g., propylene glycol) and unlike aqueous injections cannot be diluted for infusions. The differences between aqueous and